RT Journal Article
T1 HIF-Overexpression and Pro-Inflammatory Priming in Human Mesenchymal Stromal Cells Improves the Healing Properties of Extracellular Vesicles in Experimental Crohn’s Disease
A1 Gómez Ferrer, Marta
A1 Amaro Prellezo, Elena
A1 Dorronsoro, Akaitz
A1 Sánchez Sánchez, Rafael
A1 Vicente López, Ángeles
A1 Cosín Roger, Jesús
A1 Barrachina, María Dolores
A1 Baquero, María Carmen
A1 Valencia Mahón, Jaris
A1 Sepúlveda, Pilar
AB Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have therapeutic potential in the treatment of several immune disorders, including ulcerative colitis, owing to their regenerative and immunosuppressive properties. We recently showed that MSCs engineered to overexpress hypoxia-inducible factor 1-alpha and telomerase (MSC-T-HIF) and conditioned with pro-inflammatory stimuli release EVs (EVMSC-T-HIFC) with potent immunomodulatory activity. We tested the efficacy of EVMSC-T-HIFC to repolarize M1 macrophages (Mφ1) to M2-like macrophages (Mφ2-like) by analyzing surface markers and cytokines and performing functional assays in co-culture, including efferocytosis and T-cell proliferation. We also studied the capacity of EVMSC-T-HIFC to dampen the inflammatory response of activated endothelium and modulate fibrosis. Finally, we tested the therapeutic capacity of EVMSC-T-HIFC in an acute colitis model. EVMSC-T-HIFc induced the repolarization of monocytes from Mφ1 to an Mφ2-like phenotype, which was accompanied by reduced inflammatory cytokine release. EVMSC-T-HIFc-treated Mφ1 had similar effects of immunosuppression on activated peripheral blood mononuclear cells (PBMC) as Mφ2, and reduced the adhesion of PBMCs to activated endothelium. EVMSC-T-HIFc also prevented myofibroblast differentiation of TGF-β-treated fibroblasts. Finally, administration of EVMSC-T-HIFc promoted healing in a TNBS-induced mouse colitis model in terms of preserving colon length and intestinal mucosa architecture and altering the ratio of Mφ1/ Mφ2 infiltration. In conclusion, EVMSC-T-HIFC have effective anti-inflammatory properties, making them potential therapeutic agents in cell free-based therapies for the treatment of Crohn’s disease and likely other immune-mediated inflammatory diseases.
PB MPDI
SN 1422-0067
YR 2021
FD 2021-10-19
LK https://hdl.handle.net/20.500.14352/4837
UL https://hdl.handle.net/20.500.14352/4837
LA eng
NO Instituto de Salud Carlos III (ISCIII)/FEDER
NO Instituto de Salud Carlos III (ISCIII)
NO Agencia Valenciana de Innovación
NO Generalitat Valenciana/FEDER
DS Docta Complutense
RD 16 abr 2025